Many neurological disorders are associated with disturbances in neuromodulation. The clinical phenotype is generally attributed to pathological changes in the abundance of neuromodulators. The proposed research tests an alternative hypothesis: Certain disease states result from changes in the neuromodulatory response. We will specifically test the hypothesis that the respiratory network, which is normally stabilized by neuromodulators such as norepinephrine (NE), becomes disrupted by NE following exposure to intermittent hypoxia a condition which is typical for obstructive sleep apnea. The research plan proposes that the noradrenergic response is dramatically altered by subtle changes in the network configuration. Based on our preliminary data we hypothesize that the irregularities are caused by inhibitory, glycinergic and GABAergic synaptic mechanisms that lead to the dissociation neuronal ensembles. Such a de-synchronized network activation will result in low amplitude bursts in the respiratory rhythm generating network. Low amplitude bursts in turn lead to incomplete and erratic activation of respiratory motor activity thus resulting in frequency irregularities at the level of the phrenic nucleus. We will characterize these effects in the pre-Botzinger complex, an important respiratory rhythm generating area and also at the level of the motor output in freely breathing animals. Our study may have important clinical implications as it will suggest novel therapeutic strategies that do not simply aim at supplementing a deficient neuromodulator. But, instead consider dynamic changes in the modulatory response during the progression of a disease. PUBLIC HEALTH RELEVANCE: Disturbed neuromodulation is a major health problem in the context of numerous neurological disorders. The proposed research will test the hypothesis that the response to neuromodulation is not fixed, but can be altered during the progression of a disease. We will specifically study the role of neuromodulation in the respiratory network, because modulatory disturbances in this network have been associated with a number of breathing disorders and Sudden Infant Death Syndrome.